Particle bound photosensitizer molecule with reduced toxicity

ABSTRACT

A method for forming a photosensitizer product that is resistant to absorption by living tissue that may include binding a photosensitizer compound with an oxide-containing particle to provide the photosensitizer derivative having a microscale size, and mixing the photosensitizer derivative into a lotion. The microscale size of the photosensitizer derivative obstructs absorption by cell tissue.

BACKGROUND Technical Field

The present disclosure generally relates to photosensitizer molecules,and more particularly to binding photosensitizer molecules to a particleto prevent leaching into the environment and to reduce the toxicity ofthe photosensitizer molecules.

Description of the Related Art

Sunscreens are products combining several ingredients that help preventthe sun's ultraviolet (UV) radiation from reaching the skin. Two typesof ultraviolet radiation, i.e., UVA and UVB, damage the skin, age itprematurely, and increase the risk of skin cancer. It is believed thatUVB is the principle form of radiation behind sunburn, while UVA rays,which penetrate the skin more deeply, are associated with wrinkling,leathering, sagging, and other light-induced effects of aging. The mostcommon sunscreens on the market contain chemical filters that include acombination of two to six of the following active ingredients:oxybenzone, avobenzone, octisalate, octocrylene, homosalate andoctinoxate. All of the sunscreens that function as chemical filters areabsorbed by the skin, are hormone disruptors and/or are allergens.Consequently, a need exists to mitigate the harmful effects of activeingredients of sunscreens while maintaining the beneficial UV filteringproperties of the sunscreen compositions.

SUMMARY

In accordance with an one aspect of the present disclosure, a method forforming a photosensitizer product is provided that is resistant toabsorption by living tissue. In one embodiment, the method may includebinding a photosensitizer compound with an oxide-containing particle toprovide a photosensitizer derivative having a microscale size, andmixing the photosensitizer derivative into a lotion, wherein saidmicroscale size obstructs absorption by cell tissue.

In another embodiment, a method for forming a photosensitizer productthat is resistant to absorption by living tissue is provided thatincludes binding a photosensitizer derivative compound selected from thegroup consisting of octocrylene, octinoxate, homosalate, octisalate, andcombinations thereof with an oxide-containing particle. Thephotosensitizer derivative with the oxide-containing particle boundthereto has a microscale size. The method may continue with mixing thephotosensitizer derivative into a lotion. In some embodiments, themicroscale size photosensitizer derivative having the oxide-containingparticle bound thereto obstructs absorption by cell tissue.

In another embodiment, a lotion is provided that includes an activeingredient of a photosensitizer derivative compound selected from thegroup consisting of octocrylene, octinoxate, homosalate, octisalate, andcombinations thereof. The photosensitizer derivative compound is boundto an oxide-containing particle. The compound size of thephotosensitizer derivative compound that is bound to theoxide-containing particle is on a microscale. The lotion may include alotion liquid base-containing the active ingredient mixed therein.

These and other features and advantages will become apparent from thefollowing detailed description of illustrative embodiments thereof,which is to be read in connection with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The following description will provide details of preferred embodimentswith reference to the following figures wherein:

FIG. 1 is a chemical structure diagram illustrating one embodiment ofexcited state enol to keto tautomerization that is consistent withabsorbing UVA/B sunlight, in accordance with an embodiment of thepresent disclosure.

FIG. 2 is a chemical structure diagram illustrating one embodiment of aphotochemical reaction for octocrylene.

FIG. 3 is a diagram illustrating the chemical structure of octisalate.

FIG. 4 is a diagram illustrating the chemical structure of octinoxate.

FIG. 5 is a diagram illustrating the chemical structure of octocrylene.

FIG. 6 illustrates the chemical structure of homosalate.

FIG. 7A is a chemical reaction diagram that illustrates one embodimentof a scheme for the synthesis of “tetherable” octinoxate molecule forbinding to an oxide-containing particle that includes a reaction withepichlorohydrin to form a precursor that is reacted with alkyl 2-cyanateto provide the “tetherable” octinoxate, in which binding theoxide-containing particle increases the size of the particle to obstructabsorption into living tissue.

FIG. 7B is a chemical reaction diagram that illustrates one embodimentof a scheme for the synthesis of “tetherable” octinoxate for binding toan oxide-containing particle that includes a reaction with protectedethylene ether to form a precursor that is reacted with alkyl 2-cyanateto provide the “tetherable” octinoxate molecule, in which binding theoxide-containing particle increases the size of the particle to obstructabsorption into living tissue.

FIG. 7C is a chemical reaction diagram that illustrates one embodimentof a scheme for the synthesis of “tetherable” octinoxate molecule thatincludes a bromine functionalized precursor molecule, in which bindingthe oxide-containing particle increases the size of the particle toobstruct absorption into living tissue.

FIG. 8A is a chemical reaction diagram that illustrates one embodiment ascheme for the synthesis of “tetherable” octocrylene molecule forbinding to an oxide-containing particle that includes a reaction withepichlorohydrin to form a precursor that is reacted with alkyl acetateto provide the “tetherable” octocrylene, in which binding theoxide-containing particle increases the size of the particle to obstructabsorption into living tissue.

FIG. 8B is a chemical reaction diagram that illustrates one embodimentof a scheme for the synthesis of “tetherable” octocrylene for binding toan oxide-containing particle that includes a reaction with protectedethylene ether to form a precursor that is reacted with alkyl acetate toprovide the “tetherable” octocrylene molecule, in which binding theoxide-containing particle increases the size of the particle to obstructabsorption into living tissue.

FIG. 8C is a chemical reaction diagram that illustrates one embodimentof a scheme for the synthesis of “tetherable” octocrylene molecule thatincludes a bromine functionalized precursor molecule, in which bindingthe oxide-containing particle increases the size of the particle toobstruct absorption into living tissue.

FIG. 9A is a chemical reaction diagram that illustrates one embodiment ascheme for the synthesis of “tetherable” octisalate/homosalate moleculefor binding to an oxide-containing particle that includes a reactionwith epichlorohydrin, in which binding the oxide-containing particleincreases the size of the particle to obstruct absorption into livingtissue.

FIG. 9B is a chemical reaction diagram that illustrates one embodimentof a scheme for the synthesis of “tetherable” octisalate/homosalatemolecule that is formed in a reaction with protected ethylene ether, inwhich binding the oxide-containing particle increases the size of theparticle to obstruct absorption into living tissue.

FIG. 9C is a chemical reaction diagram that illustrates one embodimentof a scheme for the synthesis of “tetherable” octisalate/homosalatemolecule that includes a bromine functionalized precursor molecule, inwhich binding the oxide-containing particle increases the size of theparticle to obstruct absorption into living tissue.

FIG. 10 illustrates one embodiment of the chemical reactions for the“tetherable” photosensitizer molecules being bound to theoxide-containing particles via nucleophilic substitution chemistry, inaccordance with one embodiment of the present disclosure.

DETAILED DESCRIPTION

Detailed embodiments of the claimed structures and methods are disclosedherein; however, it is to be understood that the disclosed embodimentsare merely illustrative of the claimed structures and methods that maybe embodied in various forms. In addition, each of the examples given inconnection with the various embodiments are intended to be illustrative,and not restrictive. Further, the figures are not necessarily to scale,some features may be exaggerated to show details of particularcomponents. Therefore, specific structural and functional detailsdisclosed herein are not to be interpreted as limiting, but merely as arepresentative basis for teaching one skilled in the art to variouslyemploy the methods and structures of the present disclosure.

References in the specification to “one embodiment”, “an embodiment”,“an example embodiment”, etc., indicate that the embodiment describedmay include a particular feature, structure, or characteristic, butevery embodiment may not necessarily include the particular feature,structure, or characteristic. Moreover, such phrases are not necessarilyreferring to the same embodiment. Further, when a particular feature,structure, or characteristic is described in connection with anembodiment, it is submitted that it is within the knowledge of oneskilled in the art to affect such feature, structure, or characteristicin connection with other embodiments whether or not explicitlydescribed.

Most common sunscreens on the market contain chemical filters, which caninclude a combination of two to six of the following active ingredients:oxybenzone, avobenzone, octisalate, octocrylene, homosalate andoctinoxate. Chemical filters function by absorbing UVA/B sunlight andconverting it to vibrational energy. In some embodiments, thephotoprotective properties can be understood in terms of an initialultrafast excited state enol (identified by reference number 5) to keto(identified by reference number 10) tautomerization, as depicted inFIG. 1. This is followed by efficient internal conversion, andsubsequent vibrational relaxation to the ground state (enol) tautomer.The same principles apply to octisalate, octocrylene, octinoxate, andhomosalate photosensitizer molecules that are described herein. Forexample, the photochemical reaction of octocrylene is depicted in FIG.2.

The present disclosure generally relates to binding active ingredientsused for absorbing ultraviolet radiation, e.g., UVA and UVB radiation,to a particle to prevent leaching of the active ingredients into theenvironment and to prevent absorption of the active ingredients intoliving cells, e.g., human tissue. In some embodiments, the activeingredients that are bound to particles to reduce their toxicity inaccordance with the methods described herein may include octocrylene,octinoxate, homosalate, octisalate, and/or analogous compounds. In someembodiments, the particles that may be used to bind to theaforementioned active ingredients to reduce the toxicity may be metaloxides, such a zinc oxide (ZnO) and/or titanium dioxide (TiO₂). In otherembodiments, the particles that may be used to bind to theaforementioned active ingredients, e.g., octocrylene, octinoxate,homosalate, octisalate, and/or analogous compounds, may be ceramicmicrosphere, e.g., glass spheres, which are benign. By increasing thesize of the compound by binding it with the oxide-containing particle,the compound can be obstructed from dermal absorption by living tissue,e.g., cells.

Octisalate (C₁₅H₂₂O₃), which is also referred to as octyl salicylate or2-ethylhexyl salicylate or 2-ethylhexyl 2-hydroxybenzoate, is an esterformed by condensation of salicyclic acid with 2-ethylhexanol. FIG. 3illustrates the chemical structure of octisalate (C₁₅H₂₂O₃). In FIG. 3,Et is an ethyl (C₂H₅) group and Bu-n is an n-butyl (—C₄H₉) group. Thesalicylate portion of the molecule absorbs ultraviolet light radiation.The range of UV spectra that is covered by octisalate is UVB. Morespecifically, octisalate can absorb wavelengths ranging from 295 nm to315 nm. In other embodiments, octisalate can absorb wavelengths rangingfrom 307 nm to 315 nm. The ethylhexanol portion of the molecule is afatty alcohol, which adds emollient and oil-like properties to themolecule. In some embodiments, although octisalate absorbs UVB, it doesnot absorb UVA. Therefore, in some embodiments, octisalate may beemployed in sunscreens with other active ingredients for absorbinglight, such as oxybenzone, octinoxate, homosalate, octocrylene, and/oranalogous compounds, wherein the octisalate is used to augment UVBprotection in the sunscreen.

One or more human case studies have shown possible photoallergic orallergenic effects associated with the typical use of octisalate. Themethods and structures described herein for binding octisalate to metalinorganic particles reduce absorption of the treated octisalate intoliving tissue, hence substantially reducing or eliminating theaforementioned allergenic effects.

Octinoxate (C₁₈H₂₆O₃), which is also referred to as octylmethoxycinnamate or ethylhexyl methoxycinnamate (INCI) or(RS)-2-Ethylhexyl (2E)-3-(4-methoxyphenyl)prop-2-enoate, is an organiccompound that can be used as an active ingredient in sunscreens and lipbalms. FIG. 4 illustrates the chemical structure of octinoxate(C₁₈H₂₆O₃). In FIG. 4, Et is an ethyl (C₂H₅) group, Bu-n is an n-butyl(—C₄H₉) group, and Me is a methyl group (CH₃). Octinoxate is an esterformed from methoxycinnamic acid and (RS)-2-ethylhexanol. Similar to theoctocrylene, octinoxate can be used in sunscreens to absorb the UVBwavelengths of the UV spectra. For example, octinoxate can absorbwavelengths ranging from 280 nm to 320 nm. In some embodiments,octinoxate does not protect against UVA. Octinoxate is a widely used UVBblocking agent in the skin care industry. As noted above, octinoxate isused in sunscreens and other cosmetics to absorb UVB rays from the sun,protecting the skin from damage, but octinoxate can also be used toreduce the appearance of scars.

In some scenarios, it is believed that octinoxate can create excessreactive oxygen species that can interfere with cellular signaling,cause mutations, lead to cell death and octinoxate has been implicatedin cardiovascular disease. Further, one or more human case studies haveshown possible photoallergic or allergenic effects associated with thetypical use of octinoxate. The methods and structures described hereinfor binding octinoxate to metal inorganic particles reduce absorption ofthe treated octinoxate into living tissue, hence substantially reducingor eliminating the aforementioned side effects typically associated withoctinoxate.

Octocrylene (C₂₄H₂₇NO₂), which is also referred to as 2-ethylhexyl2-cyano-3,3-diphenyl-2-propenoate, is an ester formed by thecondensation of a diphenylcyanoacrylate with 2-ethylhexanol. FIG. 5illustrates the chemical structure of octocrylene (C₂₄H₂₇NO₂). Theextended conjugation of the acrylate portion of the octocrylene moleculeabsorbs UVB and short-wave UVA (ultraviolet) rays with wavelengths from280 to 320 nm. The ethylhexanol portion of the octocrylene molecule is afatty alcohol, adding emollient and oil-like (water resistant)properties.

It has been determined that conventional octocrylene molecules canpenetrate into the skin where they acts as a photosensitizer, whichresults in an increased production of free radicals under illumination.Free radicals are known to induce indirect DNA damage, and an increasedconcentration of free radicals might have contributed to the increasedincidence of malignant melanoma in sunscreen-users compared tonon-users. Further, one or more human case studies have shown possiblephotoallergic or allergenic effects associated with the typical use ofoctocrylene. The methods and structures described herein for bindingoctocrylene to metal inorganic particles reduce absorption of thetreated octocrylene into living tissue, hence substantially reducing oreliminating the aforementioned side effects typically associated withoctocrylene.

Homosalate (C₁₆H₂₂O₃), which is also referred to as3,3,5-Trimethylcyclohexyl 2-hydroxybenzoate, is an ester formed fromsalicylic acid and 3,3,5-trimethylcyclohexanol, a derivative ofcyclohexanol. FIG. 6 illustrates the chemical structure of homosalate(C₁₆H₂₂O₃). In some embodiments, homosalate is used as a chemical UVfilter. The salicylic acid portion of the molecule absorbs ultravioletrays with a wavelength from 295 nm to 315 nm, protecting the skin fromsun damage.

In some instances, there are possible photoallergic or allergeniceffects associated with the typical use of homosalate. The methods andstructures described herein for binding homosalate to metal inorganicparticles reduce absorption of the treated homosalate into livingtissue, hence substantially reducing or eliminating the aforementionedside effects typically associated with homosalate.

It is also noted that although the following descriptions providestitanium dioxide (TiO₂) and zinc oxide (ZnO) as examples ofoxide-containing particles that are bound to the benzophenone compound,e.g., oxybenzone compound, the present disclosure is not limited to onlythese metal oxides. In some examples, the oxide-containing particle is ametal oxide selected from the group consisting of titanium dioxide(TiO₂), tantalum oxide (Ta₂O₅), aluminum oxide (Al₂O₃), zinc oxide(ZnO), and combinations thereof. In some examples, titanium dioxide isemployed, because of the non-toxic nature of the material.

In some embodiments, the titanium dioxide employed for theoxide-containing particles may be in the form of nanoparticles, i.e.,particles having a nanoscale. In some examples, the oxide-containingparticles having the nanoscale have a diameter that ranges from 5 nm to100 nm. In other examples, the oxide-containing particles having ananoscale dimension may have a diameter ranging from 10 nm to 50 nm. Infurther examples, the oxide-containing particles having the nanoscaledimension ranging from 15 nm to 25 mm. It is noted that the diameter ofthe nanoscale particles of titanium oxide may also be equal to 5 nm, 10nm, 15 nm, 20 nm, 25 nm, 30 nm, 35 nm, 40 nm, 45 nm, 50 nm, 55 nm, 60nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm and 95 nm, as well as anyrange of dimensions including a lower limit and upper limit selectedfrom the above examples.

In some embodiments, the nanoparticles of titanium dioxide that may beprepared for binding to UV absorbing active ingredients, e.g., esters,used in sunscreen and sunblock applications, such as octisalate,octocrylene, octinoxate, and homosalate, may include nano titaniumdioxide having a particle size on the order of 20 nm and having a puritygreater than 98%. In some examples, the purity of the titanium dioxidemay be 99.5% pure.

The UV absorbing active ingredients, e.g., esters, used in sunscreen andsunblock applications, such as octisalate, octocrylene, octinoxate, andhomosalate, that are described above are bound to oxide-containingparticles to increase their size, in which their increased sizeobstructs their absorption, e.g., transdermal absorption, into livingtissue. For example, in some embodiments, the methods and structuresdisclosed herein, and described with reference to FIGS. 6-10, derivitizeoctocrylene, octinoxate, homosalate, and octisalate, or an analogouscompound, and bind the aforementioned derivitized UV absorbing activeingredient to an oxide-containing particle, e.g., zinc oxide (ZnO) ortitanium dioxide (TiO₂). These derivatives, i.e., derivitizedoctocrylene, octinoxate, homosalate, and octisalate, possess a“tetherable” chain that can be used to bind them to the oxide-containingparticles, e.g., titanium dioxide (TiO₂) and/or zinc oxide (ZnO). Thederivitized UV absorbing active ingredients may also be referred to asderivitized photosensitizer molecules. It is also noted, that inaddition to the aforementioned titanium dioxide (TiO₂) and zinc oxide(ZnO), the “tetherable” chains provided herein can also bind thephotosensitizer to ceramic microspheres (glass spheres), such as silicondioxide (SiO₂), which are benign.

FIGS. 7A-7C illustrate one embodiment of the chemical reactions for ascheme for the synthesis of “tetherable” octinoxate for binding to anoxide-containing particle, in which binding the oxide-containingparticle increases the size of the particle to obstruct absorption intoliving tissue. Referring to FIG. 7A, a hydroxyl-functionalizedprecursory molecules, i.e., benzene ring functionalized molecule,identified by reference number 1A on the left side of the reaction isreacted with epichlorohydrin (C₃H₅ClO or C₃H₅OCl) under basicconditions, e.g., in a sodium hydroxide solution (NaOH) under refluxconditions, to provide a “tetherable” precursor molecule identified byreference number 1C. In one embodiment, the hydroxyl-functionalizedprecursor molecule identified by reference number 1A is a benzylaldehyde functionalized with a hydroxide (OH) group. The “tetherable”precursor molecule identified by reference number 1C can be referred toas Benzaldehyde, 4-(2-oxiranylmethoxy)-, when n=1, and can be referredto as Benzaldehyde, 4-(2-oxiranylethoxy)-, when n=2, and so forth.

Referring to FIG. 7B, in another embodiment, the hydroxyl (OH)functionalized precursor molecule identified by reference number 1A onthe left side of the reaction is reacted with a protected ethylene etherto provide a “tetherable” precursor molecule identified by referencenumber 1D. In one embodiment, the hydroxyl-functionalized precursormolecule identified by reference number 1A is a benzyl aldehydefunctionalized with a hydroxide (OH) group. The “tetherable” precursormolecule identified by reference number 1D can be referred to asBenzaldehyde, 4-(2-bromoethoxy)-, when n=1 (C₉H₉BrO₂), and can bereferred to as Benzaldehyde, 4-(4-bromoethoxy)-, when n=2, and so forth.

More specifically, the precursor identified by reference number 1A isreacted with a [(chloroalkoxy)ethyl]trialkyl silaneidentified byreference number 1I which includes a tert-butyl dimethyl silyl([—Si(CH₃)₃]) (TBS) protecting group. In one example, the precursoridentified by reference number 1A is reacted with the[(chloroalkoxy)ethyl]trialkyl silane identified by reference number 1Ithat includes a tert-butyl dimethyl silyl (TBS) protecting group inmethyl ethyl ketone (CH₃C(0)CH₂CH₃)(MEK) solvent and potassium carbonate(K₂CO₃). In some embodiments, before the [(chloroalkoxy)ethyl]trialkylsilane identified by reference number 1I is reacted to provide the“tetherable” precursor molecule identified by reference number 1D, thesilyl protecting group can then be removed under acidic conditions andfunctionalized to provide a bromine terminated chain. For example, thesilyl protecting group may be removed using hydrochloric acid (HCl) in asolvent of tetrahydrofuran (THF) in the reaction identified by referencenumber 1J. THF is an organic solvent with the formula (CH₂)₄O. In someembodiments, the silyl protecting group is converted to a bromide. Theconversion to a bromide may include reaction with phosphorus tribromide(PBr₃) in a solution of dichloromethane (DCM) in the reaction identifiedby reference number 1K. It is noted that phosphorus tribromide (PBr₃) isonly one example of a composition for providing a bromine terminatedchain. In other examples, the composition for providing the bromineterminated chain can include phosphorus pentabromide or phosphorusoxybromide.

Referring to FIG. 7C, a bromine-functionalized precursor moleculeidentified by reference number 1B is reacted with a terminalhydroxyl-alkyne-functionalized alkyl chain identified by referencenumber 1L under Sonogashira cross-coupling conditions. The Sonogashirareaction is a cross-coupling reaction to form carbon-carbon bonds thatemploys a palladium (Pd) catalyst to form a carbon-carbon bond between aterminal alkyne and an aryl or vinyl halide.

In some embodiments, the Sonogashira cross-coupling employs twocatalysts. For example, one catalyst may be provided by a zerovalentpalladium complex and a second catalyst provided by a halide salt ofcopper(I). Examples of such palladium catalysts include compounds inwhich palladium is ligated to phosphines (Pd(PPh₃)₄). A commonderivative is Pd(PPh₃)₂Cl₂. Other examples of palladium catalystsinclude bidentate ligand catalysts, such asPd(1,2-Bis(diphenylphosphino)ethane(dppe))Cl,Pd(1,3-Bis(diphenylphosphino)propane (dppp))Cl₂, andPd(1,1′-Bis(diphenylphosphino)ferrocene)Cl₂. Examples of the secondcatalyst provided by a copper based material may include copper(I)salts, such as copper iodide, that react with the terminal alkyne andproduce a copper(I) acetylide, which acts as an activated species forthe coupling reactions. For example, Cu(I) is a co-catalyst in thereaction, and is used to increase the rate of the reaction. In oneexample, the Sonogashira cross-coupling reaction may includePd(PPh₃)₂Cl₂ and Cu(I) as identified by reference number 1M. In someembodiments, the Sonogashira cross-coupling reaction can be carried outat room temperature, e.g., 20° C. to 25° C., with a base, typically anamine, such as diethylamine (CH₃CH₂NHCH₂CH₃), which also acts as thesolvent. The reaction medium must be basic to neutralize the hydrogenhalide produced as the byproduct of this coupling reaction, soalkylamine compounds such as triethylamine and diethylamine aresometimes used as solvents, but also dimethylformamide (DMF)(CH₃)₂NC(O)H) or ether can be used as solvent.

Referring to FIG. 7C, reaction of the bromine functionalized precursormolecule identified by reference number 1B with the terminalhydroxyl-alkyne-functionalized alkyl chain identified by referencenumber 1L under the above described Sonogashira cross-couplingconditions results in the alkyl-“tetherable” photosensitizer precursormolecule identified by reference number 1E. In one embodiment, thehydroxyl-functionalized precursor molecule identified by referencenumber 1B is 4-bromo-benzaldehyde. The “tetherable” precursor moleculeidentified by reference number 1E is4-(3-bromoprop-1yn-1-yl(benzaldehyde) when n=1, and the “tetherable”precursor molecule identified by reference number 1E is4-(4-bromobut-1yn-1-yl(benzaldehyde) when n=2.

Referring to FIGS. 7A, 7B and 7C, the photosensitizer precursormolecules are then reacted with an alkyl 2-cyanoate to give “tetherable”octinoxate molecules. For example, the “tetherable” precursor moleculeidentified by reference number 1C produced from the hydroxylfunctionalized precursor identified by reference number 1A reacted withepichlorohydrin under basic conditions using the reactions depicted inFIG. 7A may be reacted with a generic ester identified by referencenumber 1N, in which R is typically 2-ethylhexyl, to produce “tetherable”octinoxate molecules, as identified by reference number 1F. In thechemical structure identified by reference number 1F in FIG. 7A, R canbe equal to, but not limited to, 2-ethylhexyl. In one embodiment, thecomposition of the “tetherable” octinoxate molecule identified byreference number 1F is 2-propenoic acid, 3-[4-(2-oxiranylmethoxy)phenyl](C₁₃H₁₄O₄), when n=1 and R═CH₃, and the composition of the “tetherable”octinoxate molecule identified by reference number 1F is 2-propenoicacid, 3-[4-(2-oxiranylethoxy)phenyl] when n=2.

Referring to the reactions depicted in FIG. 7B, the “tetherable”precursor molecule identified by reference number 1D produced from thehydroxyl functionalized precursor identified by reference number 1Areacted with a protected ethylene ether may be reacted with a genericester identified by reference number 1N, in which R is typically2-ethylhexyl, to produce “tetherable” octinoxate molecules, asidentified by reference number 1G. In one embodiment, in the“tetherable” octinoxate molecule identified by reference number 1G inFIG. 7B, R can be equal to 2-ethylhexyl, and X is equal to hydroxide(OH). In another embodiment, in the “tetherable” octinoxate moleculeidentified by reference number 1G in FIG. 7B, R can be equal to2-ethylhexyl, and X is a bromide (Br). In one embodiment, thecomposition of the “tetherable” octinoxate molecule identified byreference number 1G is 2-propenoic acid, 3-[4-(2-bromoethoxy)phenyl]-,methyl ester, (2E), when n=1, and the composition of the “tetherable”octinoxate molecule identified by reference number 1G is 2-propenoicacid, 3-[4-(2-(2-bromoethoxy)ethoxy)phenyl]-, methyl ester, (2E), whenn=2. Referring to the reactions depicted in FIG. 7C, the “tetherable”precursor molecule identified by reference number 1E produced from thebromide functionalized precursor identified by reference number 1Breacted with the terminal hydroxyl-alkyne-functionalized alkyl chainunder Sonogashira cross-coupling reactions may be reacted with a genericester identified by reference number 1N, in which R is typically2-ethylhexyl, to produce “tetherable” octinoxate molecules, asidentified by reference number 1H. In one embodiment, in the“tetherable” octinoxate molecule identified by reference number 1H inFIG. 7C, R can be equal to 2-ethylhexyl, and X is equal to hydroxide(OH). In another embodiment, in the “tetherable” octinoxate moleculeidentified by reference number 1H in FIG. 7C, R can be equal to2-ethylhexyl, and X is a bromide (Br). In one embodiment, thecomposition of the “tetherable” octinoxate molecule identified byreference number 1H is (E)-2-ethyhexyl3-(4-(4-bromobut-1-yn-1-yl)phenyl)acrylate when n=2, or the compositionof the “tetherable” octinoxate molecule identified by reference number1H is (E)-2-ethyhexyl 3-(4-(4-bromoprop-1-yn-1-yl)phenyl)acrylate whenn=1.

The generic ester identified by reference number 1N is reacted with the“tetherable” precursor molecule identified by reference numbers 1C, 1D,1E in a solution of ammonium acetate (NH₄OAC)(NH₄CH₃CO₂) and acetic acid(CH₃COOH) identified by reference number 1O, as depicted in FIGS. 7A, 7Band 7C.

Each of the “tetherable” photosensitizer molecules in the schemes forproducing the “tetherable” octinoxate molecules identified by referencenumbers 1F, 1G, 1H, as depicted in FIGS. 7A, 7B and 7C, respectively,are then bound to the oxide-containing particles, e.g., titaniumnanoparticle (TiNs), via nucleophilic substitution chemistry, asdepicted in FIG. 10. The term “nucleophilic substitution” denotes aclass of reactions in which an electron rich nucleophile selectivelybonds with or attacks the positive or partially positive charge of anatom or a group of atoms to replace a leaving group.

In one embodiment, the “tetherable” octinoxate molecules identified byreference numbers 1F, 1G, 1H, as depicted in FIGS. 7A, 7B and 7C,respectively, are bound to the surface of an oxide-containing particle20, e.g., titanium dioxide (TiO₂), as depicted in FIG. 10. It is notedthat the “tetherable” octinoxate molecules are identified to the left ofthe equation depicted in FIG. 10 by reference number 10, which can beequal to any of the compositions identified by reference numbers 1F, 1G,1H, as described above with reference to FIGS. 7A, 7B, 7C. In someembodiments, the “tetherable” octinoxate includes a terminal hydroxygroup (—OH) for binding to the oxide-containing particles 20, e.g.,titanium dioxide (TiO₂). More specifically, in some embodiments, the“tetherable” octinoxate provides for a hydroxyl-terminatedchain-functionalized octocrylene bound (in which the linking molecule isidentified by reference 25) to an oxide-containing particle, e.g.,titanium nanoparticle.

In some embodiments, hydroxyl-terminated chain-functionalized octinoxatemolecules may be dissolved or suspended in distilled water. Nano ormicro titanium dioxide (TiO₂) may be added into the octocrylenemolecules solution and may be stirred for 24 hours at room temperature,e.g., 20° C. to 25° C. The reaction mixture may contain a co-solventsuch as ethanol, isopropanol, tetrahydrofuran, or ethanol to helpdissolve the octinoxate molecules. Then the mixture may be centrifugedfor 30 min. The resulting powders may be eluted with distilled waterand, afterward, may be dried in an oven at 100° C. for 12 h. Thede-protection may be provided by reaction with sodium hydroxide (NaOH)in a solvent, such as tetrahydrofuran (THF). The deprotection andbinding reactions are identified by reference number 30.

The octinoxate molecules that are bound to the oxide-containing particleusing the method described above with reference to FIGS. 7A-7C and FIG.10 can provide an octinoxate-containing compound (identified byreference number 10a) having a size ranging from 10 μm to 100 μm. Inother examples, the size of the octinoxate-containing compound that isbound to an oxide-containing particle, such as titanium dioxide, has asize that may be equal to 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40μm, 45 μm, 50 μm, 55 μm, 60 μm, 65 μm, 70 μm, 75 μm, 80 μm, 85 μm, 90μm, 95 μm and 100 μm, as well as any range of dimensions having a lowervalue and an upper value each provided by one of the aforementionedexample dimensions.

FIGS. 8A-8C illustrates one embodiment of the chemical reactions for ascheme for the synthesis of “tetherable” octocrylene for binding to anoxide-containing particle, in which binding the oxide-containingparticle increases the size of the particle to obstruct absorption intoliving tissue. Referring to FIG. 8A, a hydroxyl-functionalized precursormolecule, i.e., a benzene ring functionalized molecule, identified byreference number 2A on the left side of the reaction, is reacted withepichlorohydrin (C₃H₅ClO or C₃H₅OCl) under basic conditions, e.g. in asodium hydroxide solution (NaOH) under reflux conditions, to provide a“tetherable” precursor molecule identified by reference number 2C. Inone embodiment, the hydroxyl-functionalized precursory moleculeidentified by reference number 2A is (4-hydroxyphenyl)-phenyl methanone.In one embodiment, the “tetherable” precursor molecule identified byreference number 2C is a methanone,[4-(2-oxiranylmethoxy)phenyl]phenyl-.

Referring to FIG. 8B, in another embodiment, the hydroxyl (OH)functionalized precursor molecule identified by reference number 2A onthe left side of the reaction is reacted with a protected ethylene etherto provide a “tetherable” precursor molecule identified by referencenumber 2D. In one embodiment, the hydroxyl-functionalized precursormolecule identified by reference number 2A is (4-hydroxyphenyl)-phenylmethanone, and the “tetherable” precursor molecule identified byreference number 2D is (4-(2-bromoethoxy)phenyl)(phenyl)methanone.

More specifically, the precursor identified by reference number 2A isreacted with [(chloroalkoxy)ethyl]trialkyl silane identified byreference number 2I that includes a tert-butyl dimethyl silyl([—Si(CH₃)₃]) (TBS) protecting group. In one example, the precursormolecule identified by reference number 2A is reacted with the[(chloroalkoxy)ethyl]trialkyl silane identified by reference number 2Ithat includes a tert-butyl dimethyl silyl (TBS) protecting group in amethyl ethyl ketone (CH₃C(O)CH₂CH₃)(MEK) solvent and potassium carbonate(K₂CO₃). In some embodiments, before the [(chloroalkoxy)ethyl]trialkylsilane identified by reference number 2I is reacted to provide the“tetherable” precursor molecule identified by reference number 2D, thesilyl protecting group can then be removed under acidic conditions andfunctionalized to provide a bromine terminated chain. For example, thesilyl protecting group may be removed using hydrochloric acid (HCl) in asolvent of tetrahydrofuran (THF) in the reaction identified by referencenumber 2J. In some embodiments, the silyl protecting group is convertedto a bromide. The conversion to a bromide may include reaction withphosphorus tribromide (PBr₃) in a solution of dichloromethane (DCM) inthe reaction identified by reference number 2K. It is noted thatphosphorus tribromide (PBr₃) is only one example of a composition forproviding a bromine terminated chain. In other examples, the compositionfor providing the bromine terminated chain can include phosphoruspentabromide or phosphorus oxybromide.

Referring to FIG. 8C, a bromine functionalized precursor moleculeidentified by reference number 2B is reacted with a terminalhydroxyl-alkyne-functionalized alkyl chain identified by referencenumber 2L under Sonogashira cross-coupling conditions that employs twocatalysts, i.e., a palladium catalyst and a copper containing catalyst.In one example, the Sonogashira cross-coupling reaction may includePd(PPh₃)₂Cl₂ and Cu(I) as identified by reference number 2M. In someembodiments, the Sonogashira cross-coupling reaction can be carried outat room temperature, e.g., 20° C. to 25° C., with a base, typically anamine, such as diethylamine (CH₃CH₂NHCH₂CH₃), which also acts as thesolvent. Referring to FIG. 8C, in some embodiments, when the reaction 2Mstops at “1:1 DMF/Et2NH”, X═OH. In other embodiments, when the reaction2M proceeds to “2. PBR₃, DCM”, as depicted in FIG. 8C, X═Br.

Referring to FIG. 8C, reaction of the bromine functionalized precursormolecule identified by reference number 2B with the terminalhydroxyl-alkyne-functionalized alkyl chain identified by referencenumber 2L under the above described Sonogashira cross-couplingconditions results in the alkyl-“tetherable” photosensitizer precursormolecule identified by reference number 2E. In one embodiment, thehydroxyl-functionalized precursor molecule identified by referencenumber 2B is a benzophenone functionalized with bromide (e.g.,Methanone, (4-bromophenyl)phenyl-), and the “tetherable” precursormolecule identified by reference number 2E is a(4-(3-bromoprop-1-yn-1-yl)phenyl(phenyl) methanone when n=1.

Referring to FIGS. 8A, 8B and 8C, the photosensitizer precursormolecules are then reacted with an alkyl 2-cyano ester to give“tetherable” octocrylene molecules. For example, the “tetherable”precursor molecule identified by reference number 2C produced from thehydroxyl functionalized precursor identified by reference number 2Areacted with epichlorohydrin under basic conditions using the reactionsdepicted the FIG. 8A may be reacted with an alkyl 2-cyano esteridentified by reference number 2N, in which R is typically 2-ethylhexyl,to produce “tetherable” octocrylenes molecules, as identified byreference number 2F. In the chemical structure identified by referencenumber 2F in FIG. 8A, R can be equal to 2-ethylhexyl. In one embodiment,the composition of the “tetherable” octocrylene molecule identified byreference number 2F is (Z)-2-ethylhexyl2-cyano-3-(4-(oxiran-2-ylmethoxy)phenyl)-3-phenyl)-3-phenylacrylate.

Referring to the reactions depicted in FIG. 8B, the “tetherable”precursor molecule identified by reference number 2D produced from thehydroxyl functionalized precursor identified by reference number 2Areacted with protected [(chloroalkoxy)methyl]trialkyl silane may bereacted with an alkyl 2-cyano ester identified by reference number 2N,in which R is typically 2-ethylhexyl, to produce “tetherable”octocrylene molecules, as identified by reference number 2G. In oneembodiment, in the “tetherable”” octocrylene molecule identified byreference number 2G in FIG. 8B, R can be equal to 2-ethylhexyl, and X isequal to hydroxide (OH). In another embodiment, in the “tetherable”octocrylene molecule identified by reference number 1G in FIG. 8B, R canbe equal to 2-ethylhexyl, and X is bromine (Br). In one embodiment, thecomposition of the “tetherable” octocrylene molecule identified byreference number 2G is (Z)-2-ethylhexyl3-(4-(2-bromoethoxy)phenyl)-2-cyano-3-phenylacrylate.

Referring to the reactions depicted in FIG. 8C, the “tetherable”precursor molecule identified by reference number 2E produced from thehydroxyl functionalized precursor identified by reference number 2Breacted with the terminal hydroxyl-alkyne-functionalized alkyl chainunder Sonogashira cross-coupling reactions may be reacted with an alkylacetate identified by reference number 2N, in which R is typically2-ethylhexyl, to produce “tetherable” octocrylenes molecules, asidentified by reference number 2H. In one embodiment, in the“tetherable” octocrylene molecule identified by reference number 2H inFIG. 8C, R can be equal to 2-ethylhexyl, and X is equal to hydroxide(OH). In another embodiment, in the “tetherable” octocrylene moleculeidentified by reference number 2H in FIG. 8C, R can be equal to2-ethylhexyl, and X is bromine (Br). In one embodiment, the compositionof the “tetherable” octocrylene molecule identified by reference number2H is (Z)-2-ethylhexyl3-(4-(3-bromoprop-1-yn-1-yl)phenyl)-2-cyano-3-phenylacrylate.

The alkyl acetate identified by reference number 2N is reacted with thetetherable precursor molecule identified by reference numbers 2C, 2D, 2Ein a solution of ammonium acetate (NH₄OAC)(NH₄CH₃CO₂) and acetic acid(CH₃COOH) identified by reference number 2O, as depicted in FIGS. 8A, 8Band 8C.

Each of the “tetherable” photosensitizer molecules in the schemes forproducing the “tetherable” octocrylenes molecules identified byreference numbers 2F, 2G, 2H, as depicted in FIGS. 8A, 8B and 8C,respectively, are then bound to the oxide-containing particles, e.g.,titanium nanoparticle (TiNs), via nucleophilic substitution chemistry.The reactions by which the “tetherable” octocrylenes bind tooxide-containing particles is similar to the reactions by which the“tetherable” octinoxate molecules identified by reference numbers 2F,2G, 2H are bound to the surface of an oxide-containing particle 20, asdepicted in FIG. 10.

For example, in some embodiments, the “tetherable” octocrylenes includea terminal hydroxy group (—OH) for binding to the oxide-containingparticles, e.g., titanium dioxide (TiO₂). More specifically, ahydroxyl-terminated chain-functionalized octocrylene molecule is boundto an oxide-containing particle, e.g., titanium nanoparticle.

In some embodiments, hydroxyl-terminated chain-functionalizedoctocrylene molecules may be dissolved or suspended in distilled water.Nano or micro titanium dioxide (TiO₂) may be added into the octocrylenemolecules solution and may be stirred for 24 hours at room temperature,e.g., 20° C. to 25° C. The reaction mixture may contain a co-solventsuch as ethanol, isopropanol, tetrahydrofuran, or ethanol to helpdissolve the octocrylene molecules. Then the mixture may be centrifugedfor 30 min. The resulting powders may be eluted with distilled waterand, afterward, may be dried in an oven at 100° C. for 12 h. Thede-protection may be provided by reaction with sodium hydroxide (NaOH)in a solvent, such as tetrahydrofuran (THF).

The octocrylene molecules that are bound to the oxide-containingparticle using the method described above with reference to FIGS. 8A-8Cand FIG. 10 can provide a octocrylene-containing compound having a sizeranging from 10 μm to 100 μm. In other examples, the size of theoctocrylene-containing compound that is bound to an oxide-containingparticle, such as titanium dioxide, has a size that may be equal to 10μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 55 μm, 60μm, 65 μm, 70 μm, 75 μm, 80 μm, 85 μm, 90 μm, 95 μm and 100 μm, as wellas any range of dimensions having a lower value and an upper value eachprovided by one of the aforementioned example dimensions.

FIGS. 9A-9C illustrates one embodiment of the chemical reactions for ascheme for the synthesis of “tetherable” homosalate/octisalate forbinding to an oxide-containing particle, in which binding theoxide-containing particle increases the size of the molecule to obstructabsorption into living tissue. In some embodiments, thehydroxyl-functionalized precursory molecules identified by referencenumber 3A in FIGS. 9A and 9B is synthesized from a commerciallyavailable benzoic acid, e.g., 2,4-dihydroxybenzoic acid. For example,the benzoic acid, e.g., 2,4-dihydroxybenzoic acid, may be reacted withROH, in which R is equal to 2-ethylhexyl, with an acid catalyst, e.g.,sulfuric acid (H₂SO₄), as depicted in FIGS. 9A and 9B. Referring to FIG.9C, in some embodiments, the bromide-functionalized precursory moleculesidentified by reference number 3B is synthesized from a commerciallyavailable benzoic acid, e.g., 4-bromo-2-hydroxybenzoic acid. Forexample, the benzoic acid, e.g., 4-bromo-2-hydroxybenzoic acid, may bereacted with ROH, in which R is equal to 3,3,5-trimethylcyclohexyl, withan acid catalyst, e.g., sulfuric acid (H₂SO₄), as depicted in FIG. 9C.

Referring to FIGS. 9A and 9B, the hydroxide-functionalized precursorymolecules identified by reference number 3A are then reacted with eitherepichlorohydrin under basic conditions, or a protected ethylene ether(separately functionalized to yield a bromine terminated chain) toprovide the “tetherable” photosensitizer, i.e., “tetherable”homosalate/octisalate, identified by molecules 3C and 3D in FIGS. 9A and9B.

Referring to FIG. 9A, the hydroxyl-functionalized precursory molecules,i.e., benzene ring-functionalized molecule, identified by referencenumber 3A on the left side of the reaction is reacted withepichlorohydrin (C₃H₅ClO or C₃H₅OCl)(identified by reference number 3N)under basic conditions, e.g. in a sodium hydroxide solution (NaOH) underreflux conditions, to provide a “tetherable” homosalate/octisalatemolecule identified by reference number 3C. In one embodiment, the“tetherable” homosalate/octisalate molecule identified by referencenumber 3C is a 2-ethylhexyl 2-hydroxy-4-(oxiran-2-ylmethoxy)benzoate.

Referring to FIG. 9B, in another embodiment, the hydroxyl(OH)-functionalized precursory molecule identified by reference number3A on the left side of the reaction is reacted with a protected ethyleneether to provide a “tetherable” homosalate/octisalate moleculeidentified by reference number 3D. More specifically, the precursoryidentified by reference number 3A is reacted with ethylene etheridentified by reference number 3I that includes a tert-butyl dimethylsilyl ([—Si(CH₃)₃]) (TBS) protecting group. In one example, theprecursory identified by reference number 3A is reacted with theethylene ether identified by reference number 3I that includes atert-butyl dimethyl silyl (TBS) protecting group in a methyl ethylketone (CH₃C(O)CH₂CH₃)(MEK) solvent and potassium carbonate (K₂CO₃). Insome embodiments, before the ethylene ether identified by referencenumber 3I is reacted to provide the “tetherable” homosalate/octisalatemolecule identified by reference number 3D, the silyl protecting groupcan be removed under acidic conditions and functionalized to provide abromine terminated chain. For example, the silyl protecting group may beremoved using hydrochloric acid (HCl) in a solvent of tetrahydrofuran(THF) in the reaction identified by reference number 3J. In someembodiments, the silyl protecting group, is converted to a bromide. Theconversion to a bromide may include reaction with phosphorus tribromide(PBr₃) in a solution of dichloromethane (DCM) in the reaction identifiedby reference number 3K. It is noted that phosphorus tribromide (PBr₃) isonly one example of a composition for providing a bromine-terminatedchain. In other examples, the composition for providing the bromineterminated chain can include phosphorus pentabromide or phosphorusoxybromide. In one embodiment, the “tetherable” homosalate/octisalatemolecule identified by reference number 3D is a 2-ethylhexyl4-(2-bromoethyoxy)benzoate.

Referring to FIG. 9C, the bromine-functionalized precursor moleculesidentified by reference number 3B are reacted with a terminalhydroxyl-alkyne-functionalized alkyl chain under Sonogashiracross-coupling conditions. This results in the alkyl-“tetherable”photosensitizer molecule 3E in FIG. 9C, which is anhomosalate/octisalate “tetherable” molecule. In one embodiment, in the“tetherable” homosalate/octisalate molecule identified by referencenumber 3E in FIG. 9C, R can be equal to 2-ethylhexyl, and X is equal tohydroxide (OH). In another embodiment, in the “tetherable”homosalate/octisalate molecule identified by reference number 3E in FIG.9C, R can be equal to 2-ethylhexyl, and X is a bromide (Br). In oneembodiment, the composition of the “tetherable” homosalate/octisalatemolecule identified by reference number 3E is 2-ethylhexyl4-(3-bromoprop-1-yn-1-yl)benzoate.

Each of the “tetherable” homosalate/octisalate “tetherable” moleculesidentified by reference numbers 3C, 3D and 3E in FIGS. 9A-9C are thenbound to the oxide-containing particle 20, e.g., titanium nanoparticle(TiNs), via nucleophilic substitution chemistry.

The reactions by which the “tetherable” homosalate/octisalate moleculesbind to oxide-containing particles is similar to the reactions by whichthe “tetherable” octinoxate molecules identified by reference numbers2F, 2G, 2H are bound to the surface of an oxide-containing particle 20,as depicted in FIG. 10.

For example, in some embodiments, the “tetherable” homosalate/octisalatemolecules include a terminal hydroxy group (—OH) for binding to theoxide-containing particles, e.g., titanium dioxide (TiO₂). Someembodiments may also include a terminal bromine group for binding to theoxide containing particles. More specifically, in some embodiments, ahydroxyl-terminated chain-functionalized homosalate/octisalate moleculeis bound to an oxide-containing particle, e.g., titanium nanoparticle.For example, hydroxyl-terminated chain-functionalized octocrylenemolecules may be dissolved or suspended in distilled water. Nano ormicro titanium dioxide (TiO₂) may be added into the octocrylenemolecules solution and may be stirred for 24 hours at room temperature,e.g., 20° C. to 25° C. The reaction mixture may contain a co-solventsuch as ethanol, isopropanol, tetrahydrofuran, or ethanol to helpdissolve the octocrylene molecules molecule. Then the mixture may becentrifuged for 30 min. The resulted powders may be eluted withdistilled water and, afterward, may be dried in an oven at 100° C. for12 h. The de-protection may be provided by reaction with sodiumhydroxide (NaOH) in a solvent, such as tetrahydrofuran (THF).

The homosalate/octisalate molecules that are bound to theoxide-containing particle using the method described above withreference to FIGS. 9A-9C and FIG. 10 can provide ahomosalate/octisalate-containing compound having a size ranging from 10μm to 100 μm. In other examples, the size of thehomosalate/octisalate-containing compound that is bound to anoxide-containing particle, such as titanium dioxide, has a size that maybe equal to 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50μm, 55 μm, 60 μm, 65 μm, 70 μm, 75 μm, 80 μm, 85 μm, 90 μm, 95 μm and100 μm, as well as any range of dimensions having a lower value and anupper value each provided by one of the aforementioned exampledimensions.

Any of the photosensitizer (e.g., octinoxate, octocrylene, homosalate,octisalate and combinations thereof) bound oxide-containing particles,e.g., titanium dioxide nanoparticles, can then be incorporated intosunscreen formulations either individually or in various mixtures. Otherparticles can be used in the place of the titanium dioxide (TiO₂)nanoparticles (TiNs) (i.e., glass microbeads) with a particle size largeenough to prevent deep penetration into the dermal layer and absorptioninto the body. In another embodiment, the particle can be functionalizedfurther at the remaining free hydroxyl groups (—OH) with other compoundsas desired for sunscreen formulations by those skilled in the arts.

The sunscreen formulations suitable for use with the methods andcompositions disclosed herein may include many combinations of syntheticand natural ingredients. A formulation is generally geared towards aspecific SPF rating or the needs of a specific consumer group. Someembodiments employed herein include oxybenzone-containing compounds thatare bound to nanoparticles of titanium dioxide for the active ingredientof the sunscreen. In addition to the sunscreening active ingredients,the formulations contemplated herein are typically emulsions such aslotions and creams, and therefore will contain several other componentsselected by the formulator from water, emulsifiers, emollients,fragrances, preservatives, vitamins, humectants, skin conditioners,antioxidants, waterproofing agents, and others. Antioxidants are oftencombined with titanium dioxide to slow down the oxidation of oils andthereby delay the deterioration of the lotion. Some examples of naturalantioxidants are vitamins E and C, rice bran oil, and sesame seed oil.Another popular antioxidant in the natural category is green tea. Somesunscreen products also contain skin soothing and moisturizing additivessuch as aloe and chamomile.

Formulating the sunscreen lotion may begin with purifying water. Reverseosmosis extracts pure, fresh water by forcing water under pressurethrough a semipermeable membrane which separates pure water moleculesfrom salts and other impurities. The active ingredients of the sunscreenlotion may then be mixed with the purified water. In some embodiments,the sunscreen lotion may be an emulsion that is formed by a processsequence that includes adding flake/powder ingredients to the oil beingused to prepare the oil phase. The active ingredients may then bedispersed in the oil phase. The photosensitizer (e.g., octinoxate,octocrylene, homosalate, octisalate and combinations thereof) boundoxide-containing particles are active ingredients. A water phasecontaining emulsifiers and stabilizers may then be prepared. The oil(including the premixed active ingredients) and water may then be mixedto form an emulsion. Forming the emulsion can be aided by heating tobetween 110° F.-185° F. (45° C.-85° C.) depending on the formulation andviscosity desired. Mixing may be continued until the desired propertiesof the end product is provided.

It is to be appreciated that the use of any of the following “/”,“and/or”, and “at least one of”, for example, in the cases of “A/B”, “Aand/or B” and “at least one of A and B”, is intended to encompass theselection of the first listed option (A) only, or the selection of thesecond listed option (B) only, or the selection of both options (A andB). As a further example, in the cases of “A, B, and/or C” and “at leastone of A, B, and C”, such phrasing is intended to encompass theselection of the first listed option (A) only, or the selection of thesecond listed option (B) only, or the selection of the third listedoption (C) only, or the selection of the first and the second listedoptions (A and B) only, or the selection of the first and third listedoptions (A and C) only, or the selection of the second and third listedoptions (B and C) only, or the selection of all three options (A and Band C). This may be extended, as readily apparent by one of ordinaryskill in this and related arts, for as many items listed.

Having described preferred embodiments of a composition and method(which are intended to be illustrative and not limiting), it is notedthat modifications and variations can be made by persons skilled in theart in light of the above teachings. It is therefore to be understoodthat changes may be made in the particular embodiments disclosed whichare within the scope of the invention as outlined by the appendedclaims. Having thus described aspects of the invention, with the detailsand particularity required by the patent laws, what is claimed anddesired protected by Letters Patent is set forth in the appended claims.

What is claimed is:
 1. A lotion comprising: an active ingredient of aphotosensitizer derivative compound selected from the group consistingof octocrylene, octinoxate, homosalate, octisalate, and combinationsthereof, wherein the photosensitizer derivative compound is bound to ametal oxide-containing particle through a tetherable structure selectedfrom the group consisting of reacted epichlorohydrin, protected ethyleneether, terminal hydroxyl-alkyne-functionalized alkyl chain,alkyl-2-cyanate, alkyl-2-cyanoate, alkyl acetate and combinationsthereof, the compound size of the photosensitizer derivative compoundthat is bound to the oxide-containing particle is on a microscale havinga diameter of up to 100 microns; and a lotion liquid base containing theactive ingredient mixed therein.
 2. The lotion of claim 1, wherein thephotosensitizer derivative compound that is bound to the metaloxide-containing particle having said microscale has a size ranging from10 microns to 100 microns.
 3. The lotion of claim 1, wherein the metaloxide-containing particle is a metal oxide selected from the groupconsisting of titanium dioxide (TiO₂), tantalum oxide (TaO₂), aluminumoxide (Al₂O₃), zinc oxide (ZnO₂), and combinations thereof.
 4. Thelotion of claim 1, wherein said microscale size of the photosensitizerderivative compound bound to the metal oxide-containing particleobstructs absorption by cell tissue.
 5. A lotion comprising: an activeingredient of a photosensitizer derivative compound bound to metaloxide-containing particle, said photosensitizer derivate compound boundwith the metal oxide-containing particle results from a reaction of afirst octinoxate precursor with epichlorohydrin to form a secondoctinoxate precursor that is reacted with alkyl 2-cyanate to provide“tetherable” octinoxate, wherein the “tetherable” octinoxate is bound tosaid metal oxide-containing particle, wherein a combined size of thephotosensitizer derivative compound and the oxide-containing particle ison a microscale having a diameter of up to 100 microns; and a lotionliquid base containing the active ingredient mixed therein.
 6. Thelotion of claim 5, wherein said microscale size ranges from 10 micronsto 100 microns.
 7. The lotion of claim 5, wherein said microscale sizeobstructs transdermal absorption of the photosensitizer derivativecompound by cell tissue.
 8. The lotion of claim 5, wherein the metaloxide of the metal-oxide containing particle is selected from the groupconsisting of titanium dioxide (TiO₂), tantalum oxide (TaO₂), aluminumoxide (Al₂O₃), zinc oxide (ZnO₂), and combinations thereof.
 9. A lotioncomprising: an active ingredient of a photosensitizer derivativecompound selected from the group consisting of octocrylene, octinoxate,homosalate, octisalate, and combinations thereof; an oxide-containingparticle bound to the photosensitizer derivative through a tetherablestructure selected from the group consisting of reacted epichlorohydrin,protected ethylene ether, terminal hydroxyl-alkyne-functionalized alkylchain, alkyl-2-cyanate, alkyl-2-cyanoate, alkyl acetate and combinationsthereof, wherein the oxide-containing particle is a metal oxide selectedfrom the group consisting of titanium dioxide (TiO₂), tantalum oxide(TaO₂), aluminum oxide (Al₂O₃), zinc oxide (ZnO₂), and combinationsthereof, the combined size of the photosensitizer derivative compoundand the oxide-containing particle is on a microscale having a diameterof up to 100 microns; and a lotion liquid base containing the activeingredient mixed therein.
 10. The lotion of claim 9, wherein thephotosensitizer derivative compound that is bound to theoxide-containing particle having said microscale has a size ranging from10 microns to 100 microns.
 11. The lotion of claim 10, wherein saidmicroscale size of the photosensitizer derivative compound bound to theoxide-containing particle obstructs absorption by cell tissue.